Neuroprotective effect of vildagliptin against cerebral ischemia in rats

Abstract

Stroke is the leading cause of death worldwide. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of anti-diabetic drugs for treatment of type-2 diabetes mellitus. The aim of this study is to evaluate the possible neuroprotective effect of a dipeptidyl peptidase-4 inhibitor, vildagliptin, independent of its anti-diabetic properties in non-diabetic rats subjected to cerebral ischemia. Anesthetized Wistar rats were subjected to either left middle cerebral artery occlusion (MCAO) or sham operation followed by reperfusion after 30 min of MCAO. The other three groups were orally administered vildagliptin at 3 dose levels (2.5, 5, 10 mg/kg) for 3 successive weeks before subjected to left focal cerebral ischemia/reperfusion and till the end of the study. Neurological deficit scores and motor activity were assessed 24 h following reperfusion. Forty-eight hours following reperfusion, rats were euthanized and their left brain hemispheres were harvested and used in biochemical, histopathological, and immunohistochemical investigations. Vildagliptin pretreatment improved neurological deficit score, locomotor activity, and motor coordination in MCAO rats. Moreover, vildagliptin reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), phosphotylinosital 3 kinase (PI3K), phosphoryated of protein kinase B (p-AKT), and mechanistic target of rapamycin (mTOR) brain contents in addition to reducing protein expression of caspase-3. Also, vildagliptin showed a dose-dependent attenuation in neuronal cell loss and histopathological alterations in MCAO rats. This study proves that vildagliptin exerted a neuroprotective effect in a dose-dependent manner as shown in the attenuation of the infarct area, neuronal cell loss, and histopathological damage in MCAO rats, which may be mediated by attenuating neuronal and motor deficits, its antioxidant property, activation of the PI3K/AKT/mTOR pathway, and its anti-apoptotic effect.

Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF‐κB Signaling Pathway

“…Recently, the cardioprotection of Vilda was determined in diabetic hearts exposed to I/R injury by attenuating the myocardial I/R damage through reduction of oxidative stress and mitochondrial dysfunction [ 20 ]. Moreover, the neuroprotective effect of Vilda was evident against cerebral ischemia through reduction of the apoptotic executive caspase, caspase-3 protein expression, and modulating oxidative stress markers in the brain [ 21 ].…”

Renoprotective effect of vildagliptin following hepatic ischemia/reperfusion injury

“…Similarly, vildagliptin or sitagliptin showed a renoprotective effect against renal I/R injury in rats via significant reduction of oxidative stress and inflammatory markers confirming their antioxidant and anti-inflammatory effects [10,25,26]. Furthermore, it was documented that the vildagliptin has cardio-and neuroprotective effect in models of myocardial and cerebral I/R, respectively, due to its ability to reduce the oxidative stress markedly proving its antioxidant activity [27,28]. This study documented for the first time the vildagliptin renoprotective effect in renal injury following hepatic IR through suppression of oxidative stress and inflammation.…”

“…The renoprotective effect of the DPP-4 inhibitors including vildagliptin may be attributed to the increased level of GLP-1 resulting in its antioxidant, anti-inflammatory, antifibrotic, and antiapoptotic effects [8,26,28,45,46]. The elevated levels of GLP-1 and its receptor GLP-1R were reported as a protective action of vildagliptin in models of diabetic nephropathy [45] and myocardial infarction [47].…”

“…The limitations of our study included: the use of a single dose of vildagliptin and this was based on the fact that this dose showed protective effect in previous studies [10,28,48]; and a group with vildagliptin alone had not been done as the safety of vildagliptin was reported in healthy subjects in both experimental and clinical studies [48,49].…”

Benidipine can prevent liver ischemia reperfusion injury in rats: a biochemical and histopathological evaluation

“…Phospholipase A2 increases arachidonic acid production from membrane phospholipids. During IR, the cyclooxygenage-2 (COX-2) enzyme is activated and leads to release of pro-inflammatory prostaglandins and ROS from arachidonic acid [6,7]. This suggests that the use of antioxidant, anti-inflammatory drugs and calcium channel blockers may be helpful in preventing liver IR injury and related complications.…”